Phosphate-binding magnesium salts and uses thereof

ABSTRACT

The present invention provides, among other things, compositions and methods suitable for the treatment of hyperphosphatemia based on phosphate-binding magnesium salts. In some embodiments, the present invention provides compositions and methods suitable for the treatment of hyperphosphatemia based on the combination of phosphate-binding magnesium and an enteric coating.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of prior application Ser. No.12/422,012, filed Apr. 10, 2009, which is hereby incorporated byreference.

BACKGROUND OF THE INVENTION

Like other diseases for which there is no cure, chronic kidney diseasetakes an ever-increasing toll on patients who have it. As the diseaseprogresses, the kidney becomes less efficient at removing various ionsfrom the blood. Among these ions is phosphate, which can form insolubleparticles when combined with calcium. In end-stage renal disease, thefinal stage of chronic kidney disease, kidney function is so compromisedthat phosphate levels in the blood (serum) become markedly elevated.This condition, known as hyperphosphatemia, carries with it many gravehealth risks. For example, when serum phosphate and calcium levels areabove a certain threshold, hardened deposits may form throughout thebody, endangering circulation. It is therefore very important to controlserum phosphate levels in patients with end-stage renal disease.

Patients with end-stage renal disease may be advised to eat a diet lowin phosphate. However, phosphate is present at some level in almost allthe foods we eat. For this reason, phosphate binders were developed.Phosphate binders are compounds taken orally and which act in thegastrointestinal tract to bind phosphate and keep it from beingabsorbed. Phosphate binders are generally taken with each meal.Phosphate binders known in the art include, for example, various saltsof aluminum and calcium, as well as some chemically synthesizedcrosslinked polymers. There are clinical circumstances in which theadministration of aluminum or calcium salts is ill-advised. In animalmodels, certain crosslinked polymers carry with them elevated risks ofcarcinogenesis. Therefore, there is a need for safer and more effectivephosphate binders.

SUMMARY OF THE INVENTION

The present invention encompasses the discovery that certain magnesiumsalts are surprisingly effective in phosphate binding. Thus, the presentinvention provides therapeutic compositions and methods for removingphosphate from a mammalian subject based on one or morephosphate-binding magnesium salts. Among other things, phosphate-bindingmagnesium salts of the invention are particularly useful when they areused in combination with other phosphate-binders (e.g., calcium salts)in treating hyperphosphatemia. For example, a combination of a magnesiumsalt with a calcium salt may provide effective phosphate-binding whilereducing the total dose of calcium and, at the same time, providingbetter nutritional balance. Therefore, the present invention providesphosphate-binding compositions and methods that are safer and moreeffective.

In one aspect, the present invention provides a composition suitable fortreating hyperphosphatemia comprising a therapeutically effective doseof at least one calcium salt and at least one phosphate-bindingmagnesium salt. In some embodiments, the at least one phosphate-bindingmagnesium salt binds at least about 50 mg phosphate per gram magnesiumsalt.

In some embodiments, the therapeutically effective dose of at least onecalcium salt contains about 20 mg to 1200 mg of calcium. In someembodiments, the therapeutically effective dose of at least one calciumsalt contains less than about 2000 mg (e.g., less than about 1800 mg,less than about 1600 mg, less than about 1400 mg, less than about 1200mg, less than about 1000 mg, less than about 800 mg, less than about 600mg, less than about 400 mg, less than about 200) of calcium.

In some embodiments, the therapeutically effective dose of at least onephosphate-binding magnesium salt contains about 20 mg to 1200 mgmagnesium. In some embodiments, the therapeutically effective dose of atleast one phosphate-binding magnesium salt comprises less than about1200 mg magnesium.

In some embodiments, the at least one calcium salt is selected from thegroup consisting of calcium acetate, calcium aceturate, calcium adipate,calcium alaninate, calcium alginate, calcium aminobutyrate, calciumarginate, calcium ascorbate, calcium aspartate, calcium benzoate,calcium besylate, calcium betainate, calcium bromide, calcium buteprate,calcium butyrate, calcium caproate, calcium carbesilate, calciumcarbonate, calcium carboxymethylcellulose, calcium camitinate, calciumchloride, calcium ciclotate, calcium citrate, calcium cypionate, calciumenanthate, calcium esylate, calcium ethandisulfonate, calcium formate,calcium fumarate, calcium glucarate, calcium gluceptate, calciumgluconate, calcium glucuronate, calcium glutamate, calcium glycinate,calcium hippurate, calcium hyclate, calcium hydroxide, calcium iodide,calcium isethionate, calcium lactate, calcium lactobionate, calciumlevulinate, calcium lysinate, calcium malate, calcium maleate, calciummesylate, calcium metilsulfate, calcium methylsulfate, calciumnaphthoate, calcium napsylate, calcium nicotinate, calcium nitrate,calcium oleate, calcium orotate, calcium oxide, calcium oxoglurate,calcium pamoate, calcium pantothenate, calcium picolinate, calciumpivalate, calcium polygalacturonate, calcium propionate, calciumsorbate, calcium steaglate, calcium stearate, calciumstearyl-2-lactylate, calcium succinate, calcium sulfate, calciumsulfite, calcium tartrate, calcium tebutate, calcium tosylate, calciumtriflutate, calcium xinafoate, and combination thereof.

In some embodiments, the at least one phosphate-binding magnesium saltis selected from the group consisting of magnesium aminobutyrate,magnesium arginate, magnesium aspartate, magnesium betainate, magnesiumcarnitinate, magnesium glycinate, magnesium hydroxide, magnesiumlysinate, magnesium oxide, magnesium propionate, and combinationthereof.

In some embodiments, the mass ratio of the at least one calcium salt tothe at least one phosphate-binding magnesium salt is between about 100:1and about 1:100. In some embodiments, the mass ratio of the at least onecalcium salt to the at least one phosphate-binding magnesium salt isbetween about 10:1 and about 1:10. In some embodiments, the mass ratioof the at least one calcium salt to the at least one phosphate-bindingmagnesium salt is between about 3:1 and about 1:3. In some embodiments,the mass ratio of the at least one calcium salt to the at least onephosphate-binding magnesium salt is between about 2:1 and about 1:2. Insome embodiments, the mass ratio of the at least one calcium salt to theat least one phosphate-binding magnesium salt is between about 3:2 andabout 2:3. In some embodiments, the mass ratio of the at least onecalcium salt to the at least one phosphate-binding magnesium salt isbetween about 5:4 and about 4:5. In some embodiments, the mass ratio ofthe at least one calcium salt to the at least one phosphate-bindingmagnesium salt is about 1:1. In some embodiments, the mass ratio of theat least one calcium salt to the at least one phosphate-bindingmagnesium salt is about 10:9.

In some embodiments, the at least one calcium salt comprises calciumacetate, and the at least one magnesium salt comprises magnesiumglycinate.

In some embodiments, the therapeutically effective dose of calciumacetate is about 340 mg and the therapeutically effective dose ofmagnesium glycinate is about 300 mg.

In another aspect, the present invention provides a composition suitablefor treating hyperphosphatemia containing a therapeutically effectivedose of at least one phosphate-binding magnesium salt, wherein the atleast one phosphate-binding magnesium salt binds at least about 50 mg(e.g., at least about 75 mg, 100 mg, 125 mg, 150 mg, 175 mg) phosphateper gram. In some embodiments, the at least one phosphate-bindingmagnesium salt binds at least about 100 mg phosphate per gram.

In yet another aspect, the present invention provides a compositionsuitable for treating hyperphosphatemia containing a therapeuticallyeffective dose of at least one phosphate-binding magnesium salt, whereinthe at least one phosphate-binding magnesium salt is not magnesiumcarbonate. In some embodiments, the at least one phosphate-bindingmagnesium salt binds at least about 50 mg (e.g., at least about 75 mg,100 mg, 125 mg, 150 mg, 175 mg) phosphate per gram.

In some embodiments, the at least one phosphate-binding magnesium saltis selected from the group consisting of magnesium aminobutyrate,magnesium arginate, magnesium aspartate, magnesium betainate, magnesiumcarnitinate, magnesium glycinate, magnesium hydroxide, magnesiumlysinate, magnesium oxide, magnesium propionate, and combinationthereof.

In some embodiments, the therapeutically effective dose of at least onephosphate-binding magnesium salt contains about 20 mg to 1200 mgmagnesium. In some embodiments, the therapeutically effective dose of atleast one phosphate-binding magnesium salt contains less than about 1200mg magnesium.

In some embodiments, the composition further contains a calcium salt. Insome embodiments, the calcium salt is present in an amount that providesabout 20 mg to 1200 mg calcium. In some embodiments, the calcium salt ispresent in an amount that provides less than 2000 mg calcium. In someembodiments, the calcium salt is present in an amount that provides lessthan 600 mg calcium.

In still another aspect, the present invention provides a compositionsuitable for treating hyperphosphatemia consisting essentially of acalcium salt and a phosphate-binding magnesium salt. In someembodiments, the calcium salt is selected from the group consisting ofcalcium acetate, calcium aceturate, calcium adipate, calcium alaninate,calcium alginate, calcium aminobutyrate, calcium arginate, calciumascorbate, calcium aspartate, calcium benzoate, calcium besylate,calcium betainate, calcium bromide, calcium buteprate, calcium butyrate,calcium caproate, calcium carbesilate, calcium carbonate, calciumcarboxymethylcellulose, calcium carnitinate, calcium chloride, calciumciclotate, calcium citrate, calcium cypionate, calcium enanthate,calcium esylate, calcium ethandisulfonate, calcium formate, calciumfumarate, calcium glucarate, calcium gluceptate, calcium gluconate,calcium glucuronate, calcium glutamate, calcium glycinate, calciumhippurate, calcium hyclate, calcium hydroxide, calcium iodide, calciumisethionate, calcium lactate, calcium lactobionate, calcium levulinate,calcium lysinate, calcium malate, calcium maleate, calcium mesylate,calcium metilsulfate, calcium methylsulfate, calcium naphthoate, calciumnapsylate, calcium nicotinate, calcium nitrate, calcium oleate, calciumorotate, calcium oxide, calcium oxoglurate, calcium pamoate, calciumpantothenate, calcium picolinate, calcium pivalate, calciumpolygalacturonate, calcium propionate, calcium sorbate, calciumsteaglate, calcium stearate, calcium stearyl-2-lactylate, calciumsuccinate, calcium sulfate, calcium sulfite, calcium tartrate, calciumtebutate, calcium tosylate, calcium triflutate, calcium xinafoate, andcombination thereof. In some embodiments, the phosphate-bindingmagnesium salt is selected from the group consisting of magnesiumaminobutyrate, magnesium arginate, magnesium aspartate, magnesiumbetainate, magnesium carnitinate, magnesium glycinate, magnesiumhydroxide, magnesium lysinate, magnesium oxide, magnesium propionate,and combination thereof. In some embodiments, the calcium salt iscalcium acetate, and the phosphate-binding magnesium salt is magnesiumglycinate.

In some embodiments, the mass ratio of the calcium salt to thephosphate-binding magnesium salt is between about 100:1 and about 1:100.In some embodiments, the mass ratio of the calcium salt to thephosphate-binding magnesium salt is between about 10:1 and about 1:10.In some embodiments, the mass ratio of the calcium salt to thephosphate-binding magnesium salt is between about 3:1 and about 1:3. Insome embodiments, the mass ratio of the calcium salt to thephosphate-binding magnesium salt is between about 2:1 and about 1:2. Insome embodiments, the mass ratio of the calcium salt to thephosphate-binding magnesium salt is between about 3:2 and about 2:3. Insome embodiments, the mass ratio of the calcium salt to thephosphate-binding magnesium salt is between about 5:4 and about 4:5. Insome embodiments, the mass ratio of the calcium salt to thephosphate-binding magnesium salt is about 1:1. In some embodiments, themass ratio of the calcium salt to the phosphate-binding magnesium saltis about 10:9.

In some embodiments, the phosphate-binding magnesium salt is present inan amount that provides about 20 mg to 1200 mg magnesium. In someembodiments, the phosphate-binding magnesium salt is present in anamount that provides less than 1200 mg magnesium. In some embodiments,the calcium salt is present in an amount that provides about 20 mg to1200 mg calcium. In some embodiments, the calcium salt is present in anamount that provides less than 2000 mg (e.g., less than about 1800 mg,less than about 1600 mg, less than about 1400 mg, less than about 1200mg, less than about 1000 mg, less than about 800 mg, less than about 600mg, less than about 400 mg, less than about 200 mg) calcium.

Inventive compositions according to the invention can be formulated fororal administration. In some embodiments, inventive compositions areformulated as a nutritional supplement. In some embodiments, inventivecompositions of the invention can be in a form of a tablet, a cachet, ahard gelatin capsule, a soft gelatin capsule, a lozenge, suspension, ora bead.

In some embodiments, inventive compositions further contain an entericcoating. In some embodiments, the enteric coating containsacetyltributyl citrate, carbomers, cellulose acetate phthalate,cellulose acetate succinate, ethyl cellulose, guar gum, hypromelloseacetate succinate, hypromellose phthalate, polymethacrylates, polyvinylacetate phthalate, shellac, tributyl citrate, triethyl citrate, whitewax and/or zein

In some embodiments, compositions of the invention further include oneor more pharmaceutically acceptable excipients. In some embodiments,pharmaceutically acceptable excipients suitable for the inventioninclude starch, a gum, an alginate, a silicate, dextrose, gelatin,lactose, mannitol, sorbitol, sucrose, tragacanth, cellulose, methylcellulose, microcrystalline cellulose, a methylhydroxybenzoate, apropylhydroxybenzoate, polyvinylpyrrolidone and/or talc.

The present invention further provides methods of treatinghyperphosphatemia by administering to a subject in need of treatment anyone of the compositions described herein.

In one aspect, the present invention provides a method of treatinghyperphosphatemia comprising administering to a subject in need oftreatment a calcium salt and a phosphate-binding magnesium salt. In someembodiments, the phosphate-binding magnesium salt binds at least about50 mg phosphate per gram. In some embodiments, the phosphate-bindingmagnesium salt is not magnesium carbonate.

In some embodiments, the calcium salt is administered in an amount thatprovides about 20 mg to 1200 mg of calcium per dose. In someembodiments, the calcium salt is administered in an amount that providesless than about 600 mg calcium per dose. In some embodiments, thecalcium salt is administered in an amount that provides less than about2000 mg (e.g., less than about 1800 mg, less than about 1600 mg, lessthan about 1400 mg, less than about 1200 mg, less than about 1000 mg,less than about 800 mg, less than about 600 mg, less than about 400 mg,less than about 200 mg) calcium per day.

In some embodiments, the phosphate-binding magnesium salt isadministered in an amount that provides about 20 mg to 1200 mg magnesiumper dose. In some embodiments, the phosphate-binding magnesium salt isadministered in an amount that provides less than about 1200 mgmagnesium per dose. In some embodiments, the phosphate-binding magnesiumsalt is administered in an amount that provides less than about 4000 mg(e.g., less than about 3500 mg, less than about 3000 mg, less than about2500 mg, less than about 2000 mg, less than about 1500 mg, or less thanabout 1000 mg) magnesium per day.

In some embodiments, the calcium salt and phosphate-binding magnesiumsalt are administered four times a day. In some embodiments, the calciumsalt and phosphate-binding magnesium salt are administered three times aday. In some embodiments, the calcium salt and phosphate-bindingmagnesium salt are administered twice a day. In some embodiments, thecalcium salt and phosphate-binding magnesium salt are administered oncedaily.

In some embodiments, the calcium salt and phosphate-binding magnesiumsalt are administered orally.

In some embodiments, the phosphate-binding magnesium salt isadministered with an enteric coating. In some embodiments, the entericcoating contains acetyltributyl citrate, carbomers, cellulose acetatephthalate, cellulose acetate succinate, ethyl cellulose, guar gum,hypromellose acetate succinate, hypromellose phthalate,polymethacrylates, polyvinyl acetate phthalate, shellac, tributylcitrate, triethyl citrate, white wax and/or zein.

In some embodiments, the calcium salt and phosphate-binding magnesiumsalt are administered simultaneously. In some embodiments, the calciumsalt and phosphate-binding magnesium salt are administered sequentially.

In some embodiments, the calcium salt is selected from the groupconsisting of calcium acetate, calcium aceturate, calcium adipate,calcium alaninate, calcium alginate, calcium aminobutyrate, calciumarginate, calcium ascorbate, calcium aspartate, calcium benzoate,calcium besylate, calcium betainate, calcium bromide, calcium buteprate,calcium butyrate, calcium caproate, calcium carbesilate, calciumcarbonate, calcium carboxymethylcellulose, calcium carnitinate, calciumchloride, calcium ciclotate, calcium citrate, calcium cypionate, calciumenanthate, calcium esylate, calcium ethandisulfonate, calcium formate,calcium fumarate, calcium glucarate, calcium gluceptate, calciumgluconate, calcium glucuronate, calcium glutamate, calcium glycinate,calcium hippurate, calcium hyclate, calcium hydroxide, calcium iodide,calcium isethionate, calcium lactate, calcium lactobionate, calciumlevulinate, calcium lysinate, calcium malate, calcium maleate, calciummesylate, calcium metilsulfate, calcium methylsulfate, calciumnaphthoate, calcium napsylate, calcium nicotinate, calcium nitrate,calcium oleate, calcium orotate, calcium oxide, calcium oxoglurate,calcium pamoate, calcium pantothenate, calcium picolinate, calciumpivalate, calcium polygalacturonate, calcium propionate, calciumsorbate, calcium steaglate, calcium stearate, calciumstearyl-2-lactylate, calcium succinate, calcium sulfate, calciumsulfite, calcium tartrate, calcium tebutate, calcium tosylate, calciumtriflutate, calcium xinafoate, and combination thereof.

In some embodiments, the phosphate-binding magnesium salt is selectedfrom the group consisting of magnesium aminobutyrate, magnesiumarginate, magnesium aspartate, magnesium betainate, magnesiumcarnitinate, magnesium glycinate, magnesium hydroxide, magnesiumlysinate, magnesium oxide, magnesium propionate, and combinationthereof.

In some embodiments, the calcium salt and phosphate-binding magnesiumsalt are administered at a mass ratio between about 100:1 and about1:100. In some embodiments, the calcium salt and phosphate-bindingmagnesium salt are administered at a mass ratio between about 10:1 andabout 1:10. In some embodiments, the calcium salt and phosphate-bindingmagnesium salt are administered at a mass ratio between about 3:1 andabout 1:3. In some embodiments, the calcium salt and phosphate-bindingmagnesium salt are administered at a mass ratio between about 2:1 andabout 1:2. In some embodiments, the calcium salt and phosphate-bindingmagnesium salt are administered at a mass ratio between about 3:2 andabout 2:3. In some embodiments, the calcium salt and phosphate-bindingmagnesium salt are administered at a mass ratio between about 5:4 andabout 4:5. In some embodiments, the calcium salt and phosphate-bindingmagnesium salt are administered at a mass ratio of about 1:1. In someembodiments, the calcium salt and phosphate-binding magnesium salt areadministered at a mass ratio of about 10:9.

In some embodiments, the calcium salt is calcium acetate, and thephosphate-binding magnesium salt is magnesium glycinate. In someembodiments, the calcium acetate is administered at a dose of about 340mg and the magnesium glycinate is administered at a dose of about 300mg.

In yet another aspect, the present invention provides a method oftreating hyperphosphatemia by administering to a subject in need oftreatment a phosphate-binding magnesium salt, wherein thephosphate-binding magnesium salt binds at least about 50 mg phosphateper gram.

In still another aspect, the present invention provides a method oftreating hyperphosphatemia by administering to a subject in need oftreatment a phosphate-binding magnesium salt, wherein thephosphate-binding magnesium salt is not magnesium carbonate.

In some embodiments, the phosphate-binding magnesium salt isadministered in an amount that provides about 20 mg to 1200 mg magnesiumper dose. In some embodiment, the phosphate-binding magnesium salt isadministered in an amount that provides less than about 1200 mgmagnesium per dose. In some embodiments, the phosphate-binding magnesiumsalt is administered in an amount that provides less than about 4000 mg(e.g., less than about 3500 mg, less than about 3000 mg, less than about2500 mg, less than about 2000 mg, less than about 1500 mg, or less thanabout 1000 mg) magnesium per day.

In some embodiments, the phosphate-binding magnesium salt isadministered four times a day. In some embodiments, thephosphate-binding magnesium salt is administered three times a day. Insome embodiments, the phosphate-binding magnesium salt is administeredtwice a day. In some embodiments, the phosphate-binding magnesium saltis administered once daily.

In some embodiments, the phosphate-binding magnesium salt isadministered orally. In some embodiments, the phosphate-bindingmagnesium salt is administered in a form of a tablet, a cachet, a hardgelatin capsule, a soft gelatin capsule, a lozenge, suspension, or abead.

In some embodiments, the phosphate-binding magnesium salt isadministered with an enteric coating. In some embodiments, a suitableenteric coating contains acetyltributyl citrate, carbomers, celluloseacetate phthalate, cellulose acetate succinate, ethyl cellulose, guargum, hypromellose acetate succinate, hypromellose phthalate,polymethacrylates, polyvinyl acetate phthalate, shellac, tributylcitrate, triethyl citrate, white wax and/or zein.

In some embodiments, the phosphate-binding magnesium salt isadministered in combination with another phosphate binder (e.g., acalcium salt).

In some embodiments, the present invention can be used to treat asubject in need of treatment for chronic kidney disease and/or end-stagerenal disease. In some embodiments, the present invention can be used totreat a subject in need of treatment for one or more disorders ofphosphate metabolism and/or impaired phosphate transport function.

In this application, the use of “or” means “and/or” unless statedotherwise. As used in this application, the term “comprise” andvariations of the term, such as “comprising” and “comprises,” are notintended to exclude other additives, components, integers or steps. Asused in this application, the terms “about” and “approximately” are usedas equivalents. Any numerals used in this application with or withoutabout/approximately are meant to cover any normal fluctuationsappreciated by one of ordinary skill in the relevant art. In certainembodiments, the term “approximately” or “about” refers to a range ofvalues that fall within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%,12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in eitherdirection (greater than or less than) of the stated reference valueunless otherwise stated or otherwise evident from the context (exceptwhere such number would exceed 100% of a possible value).

Other features, objects, and advantages of the present invention areapparent in the detailed description, drawings and claims that follow.It should be understood, however, that the detailed description, thedrawings, and the claims, while indicating embodiments of the presentinvention, are given by way of illustration only, not limitation.Various changes and modifications within the scope of the invention willbecome apparent to those skilled in the art.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides compositions and methods for removingphosphate from a subject based on phosphate-binding magnesium salts. Insome embodiments, the present invention provides compositions andmethods for treating hyperphosphatemia using a phosphate-bindingmagnesium salt or, a combination of phosphate-binding magnesium andcalcium salts.

Various aspects of the invention are described in detail in thefollowing sections. The use of sections is not meant to limit theinvention. Each section can apply to any aspect of the invention. Inthis application, the use of “or” means “and/or” unless statedotherwise.

Phosphate-Binding Magnesium Salts

The present invention is, in part, based on the discovery of theunexpected unique features of the phosphate-binding ability of magnesiumsalts. It was common chemical knowledge that, like many metals (e.g.,calcium), the divalent cations of magnesium are capable of forminghighly insoluble salts with the phosphate anion in aqueous solutions.However, unlike calcium, the effort of developing therapeuticphosphate-binders based on magnesium salts was not successful before thepresent invention. As described below, the present inventors discoveredthat the ability of various magnesium salts to bind phosphate under acondition simulating small intestinal fluid (SIF) is surprisinglydifferent than calcium salts. It was a chemical dogma and theory that ifa salt of metallic cations that is more soluble in water than is thecorresponding phosphate salt, an insoluble phosphate salt will form whenthat salt is mixed into a solution containing phosphate. For example,the solubility of calcium chloride in 20° C. water is 745 g/L and thesolubility of calcium phosphate is 20 mg/L. Therefore, calcium chlorideis 37250 times more soluble in water. When calcium chloride is mixed inwater with phosphate, an insoluble calcium phosphate precipitate formsas expected. The solubility of magnesium chloride is 546 g/L in water,and the solubility of magnesium phosphate is 0.26 mg/L. Therefore,magnesium chloride is 2,100,000 times more soluble in water thanmagnesium phosphate. However, totally unexpectedly and unlike calcium,when a solution of magnesium chloride was mixed with a phosphatesolution simulating small intestinal fluid (SIF), no insoluble magnesiumphosphate precipitate forms. As described in the Examples section, upontesting numerous magnesium salts for their ability to form insolublemagnesium phosphate in a solution similar to SIF, the inventors of thepresent application discovered that only a few magnesium salts wouldeffectively precipitate phosphate from SIF. Result from each magnesiumsalt was unexpected.

In addition, the present inventors further discovered that magnesiumsalts and calcium salts may interact differently with stomach acid whichcontains an overwhelming amount of HCl. As described in the Examplessection, certain active magnesium salts (e.g., magnesium oxide orhydroxide) may react with stomach acid (HCl) to form magnesium chloride(which, as described above, would not be able to precipitate phosphatein SIF) and thus lose their ability to precipitate phosphate in SIF(see, Example 3). Therefore, it is desirable to enteric coat magnesiumsalts, in particular, those magnesium salts that are capable of reactingwith stomach acid (HCl) (referred to as “active magnesium salts” in thisapplication) such that magnesium salts are protected from stomach acids.Unlike magnesium, calcium salts typically will not lose its ability toprecipitate phosphate in SIF after reacting with the stomach acid (HCl)because converted calcium chloride, as described above, readilyprecipitates phosphate from SIF. Therefore, any calcium salt (acetate,carbonate, etc) absent any enteric coating should still be an effectivephosphate binder in humans.

As used herein, the term “phosphate-binding magnesium salts” refers toany magnesium-containing salts that are capable of binding,precipitating, and/or removing phosphate from a mammalian subject undera physiological condition (e.g., in small intestinal fluid) with orwithout an enteric coating. As used herein, the term “enteric coating”or “enteric film” refers to a barrier applied to, for example, oralmedication containing magnesium salts that controls the location in thedigestive system where the medication is absorbed. Typically, entericcoatings prevent release of medication before it reaches the smallintestine. In some embodiments, enteric coatings suitable for thepresent invention include surface coatings that are stable at the highlyacidic pH (e.g., pH ˜3) found in the stomach, but dissolve quickly at aless acidic (relatively more basic) pH (e.g., (above pH 5.5). In someembodiments, phosphate-binding magnesium salts suitable for theinvention include magnesium-containing salts that bind at least about 25mg (e.g., at least about 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180mg, 190 mg, or 200 mg) phosphate per gram of magnesium salt. In someembodiments, the phosphate-binding capacity of a magnesium salt can becharacterized using various phosphate-binding assays known in the art.In some embodiments, the phosphate-binding capacity of a magnesium saltis characterized in a solution simulating SIF. Exemplaryphosphate-binding assays in solutions simulating SIF are described inthe Example sections below. Additional phosphate-binding assays aredescribed in Rosenbaum et al. Nephrol. Dial. Transplant. 12:961-964(1997); and Lowry & Lopez J. Biol. Chem. 162:421-428 (1946), theteachings of which are incorporated by reference herein.

Specific phosphate binding capacity of exemplary magnesium salts aredescribed in Example 2 (see Tables 2-5).

In some embodiments, phosphate-binding magnesium salts suitable for theinvention include those magnesium salts that bind more than 25 mgphosphate per gram. Such exemplary phosphate-binding magnesium saltsinclude, but are not limited to, magnesium aminobutyrate, magnesiumarginate, magnesium aspartate, magnesium betainate, magnesiumcarnitinate, magnesium glycinate, magnesium hydroxide, magnesiumlysinate, magnesium oxide, magnesium propionate, and magnesium tartrate.

In some embodiments, phosphate-binding magnesium salts suitable for theinvention include those magnesium salts that bind more than 50 mgphosphate per gram. Such exemplary phosphate-binding magnesium saltsinclude, but are not limited to, magnesium aminobutyrate, magnesiumarginate, magnesium aspartate, magnesium betainate, magnesiumcarnitinate, magnesium glycinate, magnesium hydroxide, magnesiumlysinate, magnesium oxide, and magnesium propionate.

In some embodiments, phosphate-binding magnesium salts suitable for theinvention include those magnesium salts that bind more than 100 mgphosphate per gram. Such exemplary phosphate-binding magnesium saltsinclude, but are not limited to, magnesium arginate, magnesiumbetainate, magnesium carnitinate, magnesium glycinate, magnesiumhydroxide, magnesium lysinate, and magnesium oxide.

As described in the Examples section, certain phosphate-bindingmagnesium salts identified by the present inventors have much higherphosphate binding capacity than those existing commercial phosphatebinders, such as PhosLo® (calcium acetate) and Renagel® (sevelamerhydrochloride) (see Example 2). Thus, the present invention providesphosphate-binding magnesium salts that can be used for improved and moreeffective therapies for hyperphosphatemia.

Phosphate-Binding Calcium Salts

In some embodiments, magnesium salts can be used in combination withphosphate-binding calcium salts. Exemplary calcium salts suitable forthe present invention include, but are not limited to, calcium acetate(Phosex®, PhosLo®), calcium aceturate, calcium adipate, calciumalaninate, calcium alginate, calcium aminobutyrate, calcium arginate,calcium ascorbate (Calcichew®, Titralac®), calcium aspartate, calciumbenzoate, calcium besylate, calcium betainate, calcium bromide, calciumbuteprate, calcium butyrate, calcium caproate, calcium carbesilate,calcium carbonate, calcium carboxymethylcellulose, calcium carnitinate,calcium chloride, calcium ciclotate, calcium citrate, calcium cypionate,calcium enanthate, calcium esylate, calcium ethandisulfonate, calciumformate, calcium fumarate, calcium glucarate, calcium gluceptate,calcium gluconate, calcium glucuronate, calcium glutamate, calciumglycinate, calcium hippurate, calcium hyclate, calcium hydroxide,calcium iodide, calcium isethionate, calcium lactate, calciumlactobionate, calcium levulinate, calcium lysinate, calcium malate,calcium maleate, calcium mesylate, calcium metilsulfate, calciummethylsulfate, calcium naphthoate, calcium napsylate, calciumnicotinate, calcium nitrate, calcium oleate, calcium orotate, calciumoxide, calcium oxoglurate, calcium pamoate, calcium pantothenate,calcium picolinate, calcium pivalate, calcium polygalacturonate, calciumpropionate, calcium sorbate, calcium steaglate, calcium stearate,calcium stearyl-2-lactylate, calcium succinate, calcium sulfate, calciumsulfite, calcium tartrate, calcium tebutate, calcium tosylate, calciumtriflutate, calcium xinafoate, and mixtures or combination thereof.

The molecule weight and percentage of calcium in certain exemplarycalcium salts suitable for the present invention are shown in Table 1.

TABLE 1 Exemplary calcium salts suitable for the invention Salt ofcalcium MW Percent Ca Acetate 158.17 25.34 Alginate 195.16 10.27Ascorbate 390.32 10.27 Carbonate 100.09 40.04 Carboxymethylcellulose257.23 7.79 Carnitinate 362.5 11.06 Chloride 110.98 36.11 Citrate 498.4324.12 Gluconate 430.37 9.31 Lactate 218.22 18.37 Levulinate 270.29 14.83Orotate 350.3 11.4 Oxide 56.08 71.47 Pantothenate 476.54 8.41 Propionate186.22 21.52 D-Saccharate (D-glucarate) 248.2 16.15 Stearate 607.03 6.60Stearyl-2 lactylate 895.28 4.48 Succinate 156.15 25.67 Sulfate 136.1429.44 Sulfite 120.14 33.36 Tartrate 188.15 21.30

Phosphate-binding magnesium salts may also be used in combination withvarious other phosphate-binding agents including, but not limited to,phosphate-binding aluminium salts (e.g., aluminium hydroxide(Alucaps®)), lanthanum salts (e.g., lanthanum carbonate (Fosrenol®)),polymers (e.g., sevelamer (Renagel®, Renvela®)), and chitosan.

Treatment of Hyperphosphatemia

Phosphate-binding magnesium salts described herein can be used to bindand/or remove phosphate from a mammalian subject. In particular,phosphate-binding magnesium salts described herein can be used to treathyperphosphatemia. As used herein, the term “hyperphosphatemia” refersto a higher than normal blood level of phosphorous. In human adults, thenormal range for blood phosphorous is approximately 2.5-4.5 mg/dL (i.e.,2.5-4.5 mg/100 mL). Typically, an individual with hyperphosphatemiacondition has fasting serum phosphorus concentration higher than 5.0mg/dL (e.g., higher than 5.5 mg/dL, 6.0 mg/dL, 6.5 mg/dL, or 7.0 mg/dL).Methods for measuring phosphate concentrations are well known in theart. For example, phosphate concentrations can be measured by the methodof Lowry and Lopez, J. Biol. Chem. 162: 421-428. The hyperphosphatemiacondition, especially if present over extended periods of time, leads tosevere abnormalities in calcium and phosphorus metabolism and can bemanifested by aberrant calcification in joints, lungs, and eyes.

Hyperphosphatemia is associated with various diseases or medicalconditions including, but not limited to, diseases associated withinadequate renal function such as, for example, chronic kidney diseaseand/or end-stage renal disease, hypoparathyroidism, and other disordersof phosphate metabolism and/or impaired phosphate transport function.

Typically, a method of treating hyperphosphatemia includes administeringto a subject in need of treatment a therapeutically effective amount ofa phosphate-binding magnesium salt. In some embodiments, a method oftreating hyperphosphatemia includes administering to a subject in needof treatment a therapeutically effective amount of at least onephosphate binding magnesium salt and at least one phosphate-bindingcalcium salt. As used herein, the term “therapeutically effectiveamount” refers to an amount effective to reduce or control serumphosphate level or to treat, prevent, and/or delay the onset of thesymptom(s) caused by hyperphosphatemia when administered in a singledose or in a series of doses separated by appropriate time intervals,such as hours or days, to a subject suffering from or susceptible to adisease, disorder, and/or condition associated with hyperphosphatemia. Atherapeutically effective amount is commonly administered in a dosingregimen that may comprise multiple unit doses. An appropriate unit dosewithin an effective dosing regimen is referred to as “therapeuticallyeffective dose.”

As used herein, an “individual,” “patient” or “subject” being treatedincludes a human or a non-human such as, a non-human mammalian subjectincluding, but not limited to, a bovine, cat, dog, ferret, gerbil, goat,guinea pig, hamster, horse, mouse, nonhuman primate, pig, rabbit, rat,or sheep. As used herein, a “subject susceptible to” a disease, disorderand/or condition associated with hyperphosphatemia refers to anindividual at risk of developing hyperphosphatemia or to a patientreporting one or more of the physiological symptoms ofhyperphosphatemia, even though a diagnosis of hyperphosphatemia may nothave been made.

As used herein, the term “reduce,” “decrease,” or grammaticalequivalents, indicate values that are relative to a baselinemeasurement, such as a measurement in the same individual prior toinitiation of the treatment described herein, or a measurement in acontrol individual (or multiple control individuals) in the absence ofthe treatment described herein. A “control individual” is an individualafflicted with the same condition of hyperphosphatemia as the individualbeing treated.

As used herein, the term “treat,” “treatment,” or “treating” refers toany method used to partially or completely alleviate, ameliorate,relieve, inhibit, prevent, delay onset of, reduce severity of and/orreduce incidence of one or more symptoms or features ofhyperphosphatemia or of a particular disease, disorder, and/or conditionunderlying hyperphosphatemia. Treatment may be administered to a subjectwho does not exhibit signs of a disease and/or exhibits only early signsof the disease for the purpose of decreasing the risk of developingpathology associated with the disease. For prophylactic benefit, acomposition of the invention may be administered to a patient at risk ofdeveloping hyperphosphatemia or to a patient reporting one or more ofthe physiological symptoms of hyperphosphatemia, even though a diagnosisof hyperphosphatemia may not have been made.

The actual amount effective for a particular application will depend onthe condition being treated (e.g., the disease or disorder and itsseverity, and the age and weight of the patient to be treated) and theroute of administration. Determination of an effective amount is wellwithin the capabilities of those skilled in the art, especially in lightof the disclosure herein. For example, the effective amount for use inhumans can be determined from animal models. For example, a dose forhumans can be formulated to achieve circulating and/or gastrointestinalconcentrations that have been found to be effective in animals.

Pharmaceutical Compositions

Phosphate-binding magnesium salts may be formulated in a pharmaceuticalcomposition as described herein. When a magnesium salt is used incombination with one or more other phosphate-binding agents, themagnesium salt and the one or more other phosphate-binding agents can beformulated into one composition or into separate compositions. In someembodiments, a pharmaceutical composition according to the inventioncontains at least one magnesium salt described herein and at least onecalcium salt described herein. Magnesium salt and calcium salt may becombined at various mass or molar ratios. For example, the mass or molarratio of the calcium salt to the magnesium salt can be between about100:1 and about 1:100 (e.g., between about 50:1 and about 1:50, betweenabout 20:1 and about 1:20, between about 10:1 and about 1:10, betweenabout 5:1 and about 1:5, between about 3:1 and about 1:3, between about2:1 and about 1:2, between about 3:2 and about 2:3, between about 5:4and about 4:5). In some embodiments, the mass or molar ratio of thecalcium salt to the magnesium salt is about 1:1. In some embodiments,the mass or molar ratio of the calcium salt to the magnesium salt isabout 10:9. In some embodiments, the mass or molar ratio of the calciumsalt to the magnesium salt is about 9:10.

Typically, a composition according to the invention is formulated tocontain a therapeutically effective amount or dose of magnesium orcalcium salt. The actual amount or dose effective for a particularapplication will depend on the condition being treated (e.g., thedisease or disorder and its severity, and the age and weight of thepatient to be treated) and the route of administration. Determination ofan effective amount or dose is well within the capabilities of thoseskilled in the art, especially in light of the disclosure herein. Forexample, the effective amount or dose for use in humans can bedetermined from animal models. In some embodiments, a dose for humanscan be formulated to achieve circulating and/or gastrointestinalconcentrations that have been found to be effective in animals.

In some embodiments, a therapeutically effective dose of a calcium saltaccording to the invention may contain about 20 mg to 1200 mg of calcium(e.g., about 20 mg to about 1000 mg of calcium, about 20 mg to about 800mg of calcium, about 20 mg to about 600 mg of calcium, about 20 mg toabout 400 mg of calcium, about 20 mg to about 200 mg of calcium, about100 mg to about 300 mg of calcium, about 100 mg to about 500 mg ofcalcium, about 100 mg to about 700 mg of calcium, about 100 mg to about900 mg of calcium). In some embodiments, a therapeutically effectivedose of a calcium salt according to the invention contains less thanabout 2000 mg (e.g., less than about 1800 mg, less than about 1600 mg,less than about 1400 mg, less than about 1200 mg, less than about 1000mg, less than about 800 mg, less than about 600 mg, less than about 500mg, less than about 400 mg, less than about 300 mg, less than about 200)of calcium. In some embodiments, a therapeutically effective dose of amagnesium salt according to the invention may contain about 20 mg to1200 mg of magnesium (e.g., about 20 mg to about 1000 mg of magnesium,about 20 mg to about 800 mg of magnesium, about 20 mg to about 600 mg ofmagnesium, about 20 mg to about 400 mg of magnesium, about 20 mg toabout 200 mg of magnesium, about 100 mg to about 300 mg of magnesium,about 100 mg to about 500 mg of magnesium, about 100 mg to about 700 mgof magnesium, about 100 mg to about 900 mg of magnesium). In someembodiments, a therapeutically effective dose of a magnesium saltcontains less than about 1200 mg of magnesium (e.g., less than about1000 mg of magnesium, less than about 800 mg magnesium, less than about600 mg of magnesium, less than about 400 mg of magnesium, or less thanabout 200 mg magnesium).

In some embodiments, compositions according to the invention, whenadministered according to a suitable dosing regimen, provide atherapeutically effective amount of calcium ranging from about 60 mg toabout 4000 mg (e.g., from about 80 mg to about 3000, from about 1000 mgto about 2000 mg, from about 500 mg to about 1200 mg, from about 500 mgto about 1100 mg, from about 500 mg to about 1000 mg) per day. In someembodiments, compositions according to the invention, when administeredaccording to a suitable dosing regimen, provide less than about 2000 mg(e.g., less than about 1800 mg, less than about 1600 mg, less than about1400 mg, less than about 1200 mg, less than about 1000 mg, less thanabout 800 mg, less than about 600 mg, less than about 400 mg, or lessthan about 200 mg) calcium per day. In some embodiments, compositionsaccording to the invention, when administered according to a suitabledosing regimen, provide a therapeutically effective amount of magnesiumranging from about 60 mg to about 4000 mg (e.g., from about 80 mg toabout 3000, from about 1000 mg to about 2000 mg, from about 500 mg toabout 1200 mg, from about 500 mg to about 1100 mg, from about 500 mg toabout 1000 mg) per day. In some embodiments, compositions according tothe invention, when administered according to a suitable dosing regimen,provide more than about 500 mg (e.g., more than about 750 mg, more thanabout 1000 mg, more than about 1250 mg, more than about 1500 mg, morethan about 1750 mg, or more than about 2000 mg) magnesium per day. Insome embodiments, compositions according to the invention, whenadministered according to a suitable dosing regimen, provide less thanabout 4000 mg (e.g., less than about 3500 mg, less than about 3000 mg,less than about 2500 mg, less than about 2000 mg, less than about 1500mg, or less than about 1000 mg) magnesium per day.

Compositions according to the invention may be administered four times aday, three times a day, twice a day, once daily, once every other day,twice a week, or once a week. In some embodiments, compositionsaccording to the invention may be administered together with a meal.

Typically, a composition of the invention further includes a carrier. Acarrier suitable for the invention is also referred to as apharmaceutically acceptable carrier, a carrier-diluent, or excipient. Acarrier may be a solid, semi-solid or liquid material which acts as anexcipient, medium, and/or vehicle for chitosan. For example, acomposition of the invention can be in a solid or liquid medium. Forexample, phosphate-binding salts may be enclosed within a carrier, suchas a capsule, paper, sachet or other container. In particular, asuitable carrier, excipient, or diluent may be a starch, a gum, analginate, a silicate, dextrose, gelatin, lactose, mannitol, sorbitol,sucrose, tragacanth, cellulose, methyl cellulose, microcrystallinecellulose, a methylhydroxybenzoate, a propylhydroxybenzoate,polyvinylpyrrolidone or talc.

A composition of the invention can be formulated for administration byinjection, topically, orally, transdermally, or rectally. In someembodiments, a composition of the present invention is formulated fororal administration. For example, a composition according to theinvention may be in a form of a cachet, a hard gelatin capsule, a softgelatin capsule, an elixir, a lozenge, a pill, a powder, a sachet, asterile packaged powder, a suspension, a syrup, a tablet, a capsule,solution, or emulsion, to name but a few.

In some embodiments, a composition according to the invention maycontain an enteric coating or film. Such a formulation or composition isalso referred to as an “enterically coated” formulation or composition.As used herein, the term “enteric coating” or “enteric film” refers to abarrier applied to, for example, oral medication that controls thelocation in the digestive system where the medication is absorbed.Typically, enteric coatings prevent release of medication before itreaches the small intestine. In some embodiments, enteric coatingssuitable for the present invention include surface coatings that arestable at the highly acidic pH (e.g., pH ˜3) found in the stomach, butdissolve quickly at a less acidic (relatively more basic) pH (e.g.,(above pH 5.5). According to the present invention, an enteric film orcoating prevents dispersion of magnesium salt and/or calcium salt in theacidic environment of the lumen of the stomach. Materials suitable forenteric coatings include, but not limited to, acetyltributyl citrate,carbomers, cellulose acetate phthalate, cellulose acetate succinate,ethyl cellulose, fatty acids, guar gum, hypromellose acetate succinate,hypromellose phthalate, polymethacrylates, polyvinyl acetate phthalate,plastics, shellac, tributyl citrate, triethyl citrate, waxes (e.g.,white wax), zein and combination thereof.

In some embodiments, a composition of the invention can be a food, adrink, or a nutritional, food or dietary supplement. In one embodiment,the composition is a nutritional supplement. As used herein, “anutritional supplement” is a preparation formulated to supply nutrients(including, but not limited to, vitamins; minerals, fatty acids or aminoacids) that are missing or not consumed in sufficient quantity in aperson's or animal's diet. As used in this application, a nutritionalsupplement is also referred to as “a food supplement” or “a dietarysupplement.”

In some embodiments, the composition of the invention is a nutritionalsupplement for a person's diet. The nutritional supplement can beadministered with or without meals and can be administered once daily,twice daily, three times daily, once every other day, twice a week, oncea week, or at a variable intervals. In some embodiments, the nutritionalsupplements can be administered three times daily with meals.Supplements may be in various forms including, for example, powders,liquids, syrups, pills, encapsulated compositions, etc.

In some embodiments, the composition of the invention is a nutritionalsupplement for an animal's diet, such as, a feed or pet food used withanother feed or pet food to improve the nutritive balance or performanceof the total. Contemplated supplements include compositions that are fedundiluted as a supplement to other feeds or pet foods, offered adlibitum with other parts of an animal's ration that are separatelyavailable, or diluted and mixed with an animal's regular feed or petfood to produce a complete feed or pet food.

In another embodiment, a composition of the invention can be a treat foranimals. Treats include, for example, compositions that are given to ananimal to entice the animal to eat during a non-meal time. Contemplatedtreats for canines include, for example, dog bones. Treats may benutritional, wherein the composition comprises one or more nutrients,and may, for example, have a composition as described above for food.Non-nutritional treats encompass any other treats that are non-toxic.

Typically, phosphate-binding magnesium salts are present in thecomposition at concentrations that do not impart an odor or flavor thatcauses the intended animal to perceive the composition to beunacceptable for consumption. In many instances, a desirable odor andflavor can be achieved using aroma or flavor enhancers.

In some embodiments, the percentage of the magnesium salt(s) or thecombined mass of magnesium and calcium salts, in a composition of theinvention is at least about 0.005% by weight of the composition (e.g.,at least about 0.1%, 0.5%, 1.0%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%,10%, 15%, 20%, 25%, 30% or higher). In some embodiments, the percentageof magnesium and/or calcium salts in a composition of the inventionranges from about 0.1% to about 30% based on the weight of thecomposition. In some embodiments, the percentage of magnesium and/orcalcium salts in a composition of the invention ranges from about 0.1%to about 10% based on the weight of the composition. In someembodiments, the percentage of magnesium and/or calcium salts in acomposition of the invention ranges from about 0.2% to about 5% based onthe weight of the composition. In some embodiments, the percentage ofmagnesium and/or calcium salts in a composition of the invention rangesfrom about 0.35% to about 1.0% based on the weight of the composition.

The present invention, thus generally described, will be understood morereadily by reference to the following examples, which are provided byway of illustration and are not intended to be limiting of the presentinvention.

EXAMPLES Example 1 Phosphate-Binding Assays

Exemplary stock solutions suitable for phosphate-binding assays includethe following: phosphate-binding solution (“PBS”) containing 10 mMKH2PO4, 30 mM Na2CO3, 80 mM NaCl, as described in Rosenbaum et al.Nephrol. Dial. Transplant. 12:961-964 (1997); acetate buffer (“AB”)solution containing 0.1N acetic acid, 0.025N sodium acetate, asdescribed in Lowry & Lopez J. Biol. Chem. 162:421-428 (1946); ammoniummolybdate (“AM”) solution containing 1% ammonium molybdate in 0.05NH2SO4, as described in Lowry & Lopez; ascorbic acid (“AA”) solutioncontaining 1% ascorbic acid in H2O, as described in Lowry & Lopez.

In general, the phosphate-binding assay was conducted in 12×75 mm glasstubes. 4.0 mL PBS (which is a solution simulating SIF) and 20 mgputative phosphate binder were added to a glass tube and then mixed for1 h at room temperature. 0.1 mL supernatant was pipetted from this tubeto a new test tube. 3.0 mL AB, 0.3 mL AA and 0.3 mL AM solutions wereadded and O.D. were measured at 700 nm after 10 minutes. The assay wasshown to be linear over the range used in this example.

The phosphate binding capacity was calculated as follows (mcg stands formicrograms):((O.D. of sample×95)/O.D. of standard)×40=mcgPO4 left in solution((3800−mcgPO4 left)×50)/1000=mgPO4 bound per gram of phosphate binder

Example 2 Exemplary Phosphate-Binding Magnesium Salts

The phosphate binding capacity of various magnesium and calcium saltswere measured using the phosphate-binding assays described in Example 1.Exemplary results were shown in Tables 2-5.

TABLE 2 Exemplary phosphate-binding results Sample PO₄ binding, mg/gPhosLo ® 146.6 MgO 184.0 Mg(OH)₂ 176.2 MgCO₃ 19.0 MgSO₄•7H₂O 19.0 Mgcitrate 16.3 CaCO₃ 10.9

TABLE 3 Exemplary phosphate-binding magnesium salts Sample PO₄ binding,mg/g PhosLo ® 171 Renagel ® 85 Mg acetate 4 Mg adipate 6 Mgaminobutyrate 85 Mg arginate 121 Mg ascorbate 4 Mg aspartate 50 Mgbetainate 147 Mg carbonate 22 Mg chloride 4 Mg citrate 15 Mg carnitinate169 Mg formate 6 Mg fumarate 4 Mg glycinate 176 Mg hydroxide 182 Mglactate 15 Mg lysinate 150 Mg maleate 15 Mg nicotinate 4 Mg orotate 20Mg oxide ≧190 Mg propionate 59 Mg stearate 15 Mg succinate 18 Mg sulfate9 Mg tartrate 28

Certain phosphate-binding results of Table 3 were calculated to reflectthe phosphate-binding capacity as follows.

TABLE 4 Exemplary phosphate-binding capacity % Mg mg PO₄ bound mg PO₄bound (or % per g per g Mg or Ca Compound Ca) compound in compound Mgarginate 6.5 121 1862 Mg betainate 9.5 147 1547 Mg glycinate 14.1 1761248 Mg hydroxide 41.7 182 436 Mg lysinate 7.7 150 1948 Mg oxide 60.3190 315 PhosLo ® (25.3% Ca) 171 676 (Ca acetate)

It can be seen that certain magnesium salts have high phosphate-bindingcapacity. For example, 1 gram of Mg in some magnesium salts (e.g., Mglysinate) binds phosphate almost three times as much as 1 gram ofcalcium in PhosLo® (Ca acetate) does.

Additional results are shown in Table 5.

TABLE 5 Exemplary phosphate-binding capacity mg PO₄ bound mg PO₄ boundper g per g Mg (or Ca) Compound compound in compound PhosLo(R)(Caacetate) 161 (636, per gram Ca) Mg aminobutyrate 76 Mg arginate 118 1815Mg betainate 141 1484 Mg glycinate 177 1255 Mg lysinate 138 1792 Mgoxide 187 310 Mg malate 29

Example 3 Impact of Stomach Acid on the Phosphate-Binding Ability ofCertain Magnesium Salts

This experiment was conducted to demonstrate that stomach acid candestroy the phosphate-binding activity of a normally active magnesiumsalt. Specifically, 20 mg MgO was first reacted with 100 μL 10M HClwhich simulates the overwhelmingly acidic stomach environment. Thereacted mixture was then tested for its ability to bind phosphate in anphosphate-binding assay as described above. As shown in Table 6, MgO,which normally has a phosphate-binding capacity of about 188.5 mg/g,lost its ability to bind phosphate after the reaction with 100 μL 10MHCl. Similar results were observed with Mg(OH)₂.

TABLE 6 Exemplary results illustrating the impact of stomach acid SamplePO₄ binding, mg/g PhosLo ® 148.8 MgO 188.5 20 mg MgO + 100 μL 10M HCl 0Mg(OH)₂ 179.0 20 mg Mg(OH)₂ + 70 μL 10M HCl 0

Example 4 Composition Containing Calcium Acetate and Magnesium Glycinate

This experiment was designed to show the therapeutic and nutritionalbenefits provided by a composition of the invention that contains bothcalcium and magnesium salts. Specifically, a composition containing bothcalcium acetate and magnesium glycinate was made by mixing PhosLo®(calcium acetate) and magnesium glycinate at a mass ratio ofapproximately 1:1 (e.g., 300 mg Mg glycinate and 340 mg Ca acetate). Thephosphate binding ability of the composition was determined by thephosphate-binding assay described in Example 1 and exemplary resultswere shown in Table 7.

TABLE 7 Compound PO₄ binding, mg/g PhosLo(R) 152 Mg glycinate 182PhosLo:MgGlycinate::1:1 185

As shown in Table 7, the composition containing both PhosLo® (calciumacetate) and magnesium glycinate binds approximately 185 mg phosphateper gram, which is more effective than PhosLo® alone (which bindsapproximately 152 mg phosphate per gram) and comparable to Mg glycinatealone (which binds approximately 182 mg phosphate per gram).

A therapeutic composition is made that contains 300 mg Mg glycinate and340 mg Ca acetate per dose. Under the existing practice, a human patienttypically takes four doses of PhosLo® with each meal, three meals a day.Therefore, the patient ingests approximately 2025 mg Ca a day, whichwould result in the binding of approximately 1328 mg phosphate. If apatient instead takes four doses of the therapeutic compositioncontaining 300 mg Mg glycinate and 340 mg Ca acetate per dose with eachmeal, three meals a day, the patient would ingest about 1032 mg Ca(which binds about 677 mg phosphate), and about 508 mg Mg (which bindsabout 635 mg phosphate). Therefore, the composition containing 300 mg Mgglycinate and 340 mg Ca acetate per dose would remove about 1312 mgphosphate per day, similar to the amount of phosphate removed by PhosLo®using the existing treatment method. However, a patient treated with thecomposition containing 300 mg Mg glycinate and 340 mg Ca acetate willonly ingest 1032 mg Ca per day, which is almost only one half of the Caamount ingested by a patient per day treated by PhosLo®. Moreover, thecomposition containing 300 mg Mg glycinate and 340 mg Ca acetate perdose provides 508 mg Mg per day, a nutrient deficient in manyindividuals, while PhosLo® provides 0 mg Mg. Therefore, a therapeuticcomposition based on a combination of magnesium and calcium saltsprovides effective phosphate-binding while significantly reducingcalcium burdens in patients and, at the same time, providing nutritionalbenefits.

Example 5 Preparation of an Oral Formulation with an Enteric Coating

An oral formulation that contains calcium acetate and magnesiumglycinate is prepared as follows. Calcium acetate, magnesium glycinate,one excipient suitable for enteric coating, one or more pharmaceuticallyacceptable excipients and other appropriate ingredients (e.g., alubricant) are mixed until a degree of uniformity suitable forpharmaceutical formulation is reached. The mixture is shaped intotablets or caplets. Tablets or caplets are then coated with at least oneexcipient suitable for enteric coating using standard methods.

Example 6 Treatment of Hyperphosphatemia

An oral formulation containing calcium acetate and magnesium glycinateprepared as described in Example 5 is used to treat human patientssuffering from hyperphosphatemia. The first patient has a serumphosphorus level between about 5.5 and about 7.5 mg/dL and has not takena phosphate binder. Two units of the formulation are orally administeredto the patient three times daily with meals. The second patient has aserum phosphorus level between about 7.5 and about 9.0 mg/dL and has nottaken a phosphate binder. Three units of the same formulation are orallyadministered to the patient three times daily with meals. The thirdpatient has a serum phosphorus level greater than about 9.0 mg/dL andhas not taken a phosphate binder. Four units of the formulation areorally administered to the patient three times daily with meals. Thefourth patient has been taking one 667-mg calcium acetate tablet permeal. One unit of the formulation is orally administered to the fourthpatient three times daily with meals, instead of the one 667-mg calciumacetate tablet per meal. The fifth patient has been taking two 667-mgcalcium acetate tablets per meal. Two units of the formulation areorally administered to the patient three times daily with meals, insteadof the two 667-mg calcium acetate tablets per meal. The sixth patienthas been taking three 667-mg calcium acetate tablets per meal. Threeunits of the formulation are orally administered to the patient threetimes daily with meals, instead of the three 667-mg calcium acetatetablets per meal.

In each of the above cases, the patient's serum phosphorus level isreduced to and remains in the range from 3.5 to 5.5 mg/dL aftertreatment according to the dosing regimen described above. A dosingregimen can be maintained relatively unchanged when the serum phosphoruslevel is within the range of 3.5 to 5.5 mg/dL.

EQUIVALENTS

The foregoing has been a description of certain non-limiting embodimentsof the invention. Those skilled in the art will recognize, or be able toascertain using no more than routine experimentation, many equivalentsto the specific embodiments of the invention described herein. Those ofordinary skill in the art will appreciate that various changes andmodifications to this description may be made without departing from thespirit or scope of the present invention, as defined in the followingclaims.

In the claims articles such as “a,”, “an” and “the” may mean one or morethan one unless indicated to the contrary or otherwise evident from thecontext. Claims or descriptions that include “or” between one or moremembers of a group are considered satisfied if one, more than one, orall of the group members are present in, employed in, or otherwiserelevant to a given product or process unless indicated to the contraryor otherwise evident from the context. The invention includesembodiments in which exactly one member of the group is present in,employed in, or otherwise relevant to a given product or process. Theinvention also includes embodiments in which more than one, or all ofthe group members are present in, employed in, or otherwise relevant toa given product or process. Furthermore, it is to be understood that theinvention encompasses all variations, combinations, and permutations inwhich one or more limitations, elements, clauses, descriptive terms,etc., from one or more of the claims or from relevant portions of thedescription are introduced into another claim. For example, any claimthat is dependent on another claim can be modified to include one ormore limitations found in any other claim that is dependent on the samebase claim. Furthermore, where the claims recite a composition, it is tobe understood that methods of using the composition for any of thepurposes disclosed herein are included, and methods of making thecomposition according to any of the methods of making disclosed hereinor other methods known in the art are included, unless otherwiseindicated or unless it would be evident to one of ordinary skill in theart that a contradiction or inconsistency would arise. In addition, theinvention encompasses compositions made according to any of the methodsfor preparing compositions disclosed herein.

Where elements are presented as lists, e.g., in Markush group format, itis to be understood that each subgroup of the elements is alsodisclosed, and any element(s) can be removed from the group. It is alsonoted that the term “comprising” is intended to be open and permits theinclusion of additional elements or steps. It should be understood that,in general, where the invention, or aspects of the invention, is/arereferred to as comprising particular elements, features, steps, etc.,certain embodiments of the invention or aspects of the inventionconsist, or consist essentially of, such elements, features, steps, etc.For purposes of simplicity those embodiments have not been specificallyset forth in haec verba herein. Thus for each embodiment of theinvention that comprises one or more elements, features, steps, etc.,the invention also provides embodiments that consist or consistessentially of those elements, features, steps, etc.

Where ranges are given, endpoints are included. Furthermore, it is to beunderstood that unless otherwise indicated or otherwise evident from thecontext and/or the understanding of one of ordinary skill in the art,values that are expressed as ranges can assume any specific value withinthe stated ranges in different embodiments of the invention, to thetenth of the unit of the lower limit of the range, unless the contextclearly dictates otherwise. It is also to be understood that unlessotherwise indicated or otherwise evident from the context and/or theunderstanding of one of ordinary skill in the art, values expressed asranges can assume any subrange within the given range, wherein theendpoints of the subrange are expressed to the same degree of accuracyas the tenth of the unit of the lower limit of the range.

In addition, it is to be understood that any particular embodiment ofthe present invention may be explicitly excluded from any one or more ofthe claims. Any embodiment, element, feature, application, or aspect ofthe compositions and/or methods of the invention can be excluded fromany one or more claims. For purposes of brevity, all of the embodimentsin which one or more elements, features, purposes, or aspects isexcluded are not set forth explicitly herein.

INCORPORATION OF REFERENCES

All publications and patent documents cited in this application areincorporated by reference in their entirety to the same extent as if thecontents of each individual publication or patent document wereincorporated herein.

1. A method of treating hyperphosphatemia comprising administering to asubject in need of treatment a composition comprising a therapeuticallyeffective dose of magnesium glycinate salt, wherein the magnesiumglycinate is characterized with an ability to bind at least about 50 mgphosphate per gram in an in vitro phosphate-binding assay, and whereinthe composition is formulated for oral administration and furtherwherein the composition comprises an enteric coating.
 2. The method ofclaim 1, wherein the therapeutically effective dose of magnesiumglycinate comprises about 20 mg to 1200 mg magnesium.
 3. The method ofclaim 1, wherein the therapeutically effective dose of magnesiumglycinate comprises less than about 200 mg magnesium.
 4. The method ofclaim 1, wherein the therapeutically effective dose comprises about 300mg of magnesium glycinate.
 5. The method of claim 1, wherein thecomposition is in a form of a tablet, a cachet, a hard gelatin capsule,a soft gelatin capsule, a lozenge, suspension, or a bead.
 6. The methodof claim 1, wherein the enteric coating prevents the magnesium glycinatefrom reacting with stomach acid to form magnesium chloride.
 7. Themethod of claim 1, wherein the enteric coating comprises acetyltributylcitrate, carbomers, cellulose acetate phthalate, cellulose acetatesuccinate, ethyl cellulose, guar gum, hypromellose acetate succinate,hypromellose phthalate, polymethacrylates, polyvinyl acetate phthalate,shellac, tributyl citrate, triethyl citrate, white wax and/or zein. 8.The method of claim 1, wherein the composition further comprises anutrient.
 9. The method of claim 8, wherein the nutrient is selectedfrom vitamins, minerals, fatty acids, and/or amino acids.
 10. A methodfor treating hyperphosphatemia in a subject, the method comprisingadministering to the subject a composition comprising a therapeuticallyeffective dose of magnesium glycinate, wherein the magnesium glycinateis characterized with an ability to bind at least about 50 mg phosphateper gram in an in vitro phosphate-binding assay, and a barrier thatprevents conversion of the magnesium glycinate to magnesium chloride.11. The method of claim 10, wherein the composition is formulated fororal administration.
 12. The method of claim 10, wherein the barrierprevents release of the magnesium glycinate before it reaches the smallintestine.
 13. The method of claim 12, wherein the barrier is a surfacecoating that is stable at pH less than 3 but dissolves at a pH above5.5.
 14. The method of claim 13, wherein the surface coating is anenteric coating.
 15. The method of claim 10, wherein the therapeuticallyeffective dose of magnesium glycinate comprises about 20 mg to 1200 mgmagnesium.
 16. The method of claim 10, wherein the composition furthercomprises a nutrient.
 17. The method of claim 16, wherein the nutrientis selected from vitamins, minerals, fatty acids, and/or amino acids.18. The method of claim 1, wherein the magnesium glycinate binds atleast about 100 mg phosphate per gram in an in vitro phosphate-bindingassay.